Abstract:The interaction of acute myeloid leukemia (AML) blasts with the leukemic microenvironment is postulated to be an important mediator of resistance to chemotherapy and disease relapse. We hypothesized that inhibition of the CXCR4/CXCL12 axis by the small molecule inhibitor, plerixafor, would disrupt the interaction of leukemic blasts with the environment and increase the sensitivity of AML blasts to chemotherapy. In this phase 1/2 study, 52 patients with relapsed or refractory AML were treated with plerixafor in… Show more
“…Similar to our observations, Uy et al 21 observed an increase in CXCR4 expression in patients dosed with the CXCR4 inhibitor plerixafor, which is also known to mobilize cells into circulation 22. The apparent increase of surface CXCR4 could be due to an upregulation of CXCR4 or due to the mobilization of a cell population with high levels of surface CXCR4 into the peripheral circulation.…”
“…Similar to our observations, Uy et al 21 observed an increase in CXCR4 expression in patients dosed with the CXCR4 inhibitor plerixafor, which is also known to mobilize cells into circulation 22. The apparent increase of surface CXCR4 could be due to an upregulation of CXCR4 or due to the mobilization of a cell population with high levels of surface CXCR4 into the peripheral circulation.…”
“…Our group and others previously demonstrated that targeting the SDF-1α/CXCR4 axis by CXCR4 inhibition can ameliorate resistance of AML cells to chemotherapy in vitro, in vivo, and in clinical trials (8,9,37). To further explore the mechanism of targeting CXCR4, we evaluated the expression of miRNAs, which have been reported to be differentially expressed and deregulated in pathophysiological conditions such as cancers.…”
We examined the role of microRNAs (miRNAs) in targeting the stromal-derived factor 1α/CXCR4 (SDF-1α/ CXCR4) axis to overcome chemoresistance of AML cells. Microarray analysis of OCI-AML3 cells revealed that the miRNA let-7a was downregulated by SDF-1α-mediated CXCR4 activation and increased by CXCR4 inhibition. Overexpression of let-7a in AML cell lines was associated with decreased c-Myc and BCL-XL protein expression and enhanced chemosensitivity, both in vitro and in vivo. We identified the transcription factor Yin Yang 1 (YY1) as a link between SDF-1α/CXCR4 signaling and let-7a, as YY1 was upregulated by SDF-1α and downregulated by treatment with a CXCR4 antagonist. ChIP assay confirmed the binding of YY1 to unprocessed let-7a DNA fragments, and treatment with YY1 shRNA increased let-7a expression. In primary human AML samples, high CXCR4 expression was associated with low let-7a levels. Xenografts of primary human AML cells engineered to overexpress let-7a exhibited enhanced sensitivity to cytarabine, resulting in greatly extended survival of immunodeficient mice. Based on these data, we propose that CXCR4 induces chemoresistance by downregulating let-7a to promote YY1-mediated transcriptional activation of MYC and BCLXL in AML cells.
“…4,36,37,59 In fact, lenalidomide mediated the mobilization of AML cells to PB through downregulation of CXCR4 in non-del5q/5q AML cells but does not affect either the expression or the production of its ligand SDF1 by BM-MSCs. In contrast to plerixafor, lenalidomide does not mobilize normal CD34 + HSPCs to PB.…”
Section: Discussionmentioning
confidence: 99%
“…Importantly, in contrast to plerixafor, IMiDs do not chemosensitize AML blasts to chemotherapy, further supporting that the addition of IMiDs to cytotoxic chemotherapy seems not feasible in AML. 36,59 Lenalidomide-attenuated pro-inflammatory cytokines including TNFα, γIFN, IL1β and macrophage inhibitory factor (MIF) have been previously described to interact with master pathways/molecules such as CXCR4-SDF1 axis, collagenases, integrins and eicosanoids in controlling cell migration and mobilization. 60-63 Thus, the immunomodulatory effects exerted by IMiDs seem to influence the BM niche in a way non-del5q/5q AML cells physically detach from BM stroma.…”
Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of non-del5q/5q- AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes non-del5q/5q- AML cells, but not healthy CD34+ cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML.
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